DESCRIPTION The Diabetes Control and Complications Trial Research Group studies demonstrated that while aggressive therapeutic efforts aimed at restoring relative euglycemia diminish complications in the microvasculature, no significant reduction in the incidence of microvascular disease was observed. These findings support the concept that factors unique to diabetes contribute to accelerated vascular disease. Many studies have demonstrated increased levels of plasma homocyst(e)ine in patients with diabetes and/or renal failure, and in patients with certain genetic mutations of genes encoding enzymes critical for metabolism of methionine and homocysteine. Indeed, elevated levels of plasma homocysteine have been linked to increased vascular disease. An important facet of hyperhomocyst(s)inemia (HHCy) is potential reversibility with vascular disease. An important facet of hyperhomocyst(s)inemia (HHCy) is its potential reversibility with increased intake of vitamins, such as folate, pyridoxine, and B12. An important question, yet to be tested in long-term human studies, is whether dietary vitamin supplementation may ameliorate the incidence of accelerate atherosclerotic vascular disease in patients with HHCy. Our laboratory has developed models of accelerated diabetic atherosclerosis in mice in which both lipid-dependent and -independent mechanisms contribute, thereby allowing us to dissect the contribution of specific factors in the development of accelerated vascular disease. We propose that upon enriching normal mouse chow with methionine, along with significant reduction of vitamins, we may test the hypothesis that accelerated vascular disease will ensue as a consequence of HHCy. In subsequent experiments, increased dietary supplementation of vitamins folic acid, pyridoxine and B12 may then serve to determine if vitamin supplementation may confer vascular-protection.